Kinetics of Immune Reconstitution in Event-Free Patients: Establishing Reference Values for Immune Recovery of Patients Receiving Allogeneic Hematopoietic Stem Cell Transplantation

Background: Immune reconstitution (IR) is strongly associated with clinical outcomes after hematopoietic stem cell transplantation (HSCT). So far, there are no optimal reference values for recovered immune cell subsets after HSCT, and approaches to enhance post-transplant IR based on data from health donors have their limitations. Therefore, reference values need to be established for immune cell counts to monitor IR and identify high-risk patients needing aggressively supportive treatment.

Methods: Between January 2011 and December 2013, 706 consecutive patients who received HLA-matched sibling transplantation (MSDT) or haploidentical transplantation (haplo-SCT) modality participated in this study. Finally a total of 144 patients who did not experience transplant complications such as poor graft function, grades II-IV acute graft-versus-host disease (GVHD), serious chronic GVHD, serious bacterial infection, invasive fungal infection, relapse or death in the first year after transplant were available for immune cell subset testing between day 30 and 365, and were analyzed in this study. To provide reference values that could be used for all recipients, the effects of recipient age, gender, and underlying disease on IR were investigated. In addition, 41 healthy donors underwent single time-point immune analysis, and the data were used as a normal control.

Results: The 4-year probability of relapse, non-relapse mortality, leukemia-free survival, and overall survival was 5% (95% CI: 1%-9%), 1% (95% CI: 0%-2%), 95% (95% CI: 90%-99%), and 98% (95% CI: 96%-100%), respectively. Monocytes recovered rapidly and persisted at higher levels than normal during the first year after transplantation. The total CD3⁺ T cell counts were very low in the first 30 days but normalized by 90 days post-transplant. CD4⁺ helper T cells recovered very slowly and did not reach normal range by 1 year after transplantation. The absolute numbers of CD8⁺ T cells were higher after 90 days post-transplant compared to healthy donors. The recovery of CD19⁺ B cells was delayed during 1 year after transplantation. All immune cell subsets except monocytes recovered faster after MDST than haplo-SCT. By univariate and multivariate analysis, the haplo-SCT modality was confirmed to be associated with immune recovery. So the reference values for recovered immune cell subgroups were provided for MSDT and haplo-SCT, respectively.

Conclusion: Our results suggest that patients with IR comparable to the reference values could have superior survival and the immune cells may not have to recover to healthy donor levels in the first year after transplantation. We emphasize that data from this recipient cohort should be understood as reference values for immune cell counts post-transplant for patients receiving HSCT.

Acknowledgments: This work was supported, in part, by the National High Technology Research and Development Program of China (Program 863; Grant No. 2013AA020401) and the National Natural Science Foundation of China (Grant No. 81470342). We thank the faculty members who collected samples and analyzed the flow cytometry data.